genetics

Stem cell researchers at UConn Health have reversed Prader-Willi syndrome in brain cells growing in the lab, findings they recently published in Human Molecular Genetics.

The discovery provides clues that could lead to a treatment for Prader-Willi, a genetic disorder that occurs in about one out of every 15,000 births, and is the most common genetic cause of life-threatening childhood obesity.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The gene is silenced because it is on the part of their chromosome they inherited from their mother, and for mysterious reasons our cells use the father’s copy of this gene. But if the father’s copy is missing, the cells can’t express that gene at all.

UConn Health’s Maeva Langouet, a post-doctoral fellow; Marc Lalande, professor emeritus of genetics and genome sciences; and their colleagues wondered if it was possible to reverse the silencing of the mother’s copy.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The researchers noticed that a certain protein, called ZNF274, was involved in the process. It silences many other genes as well, but in those cases it usually acts with another protein. On the Prader-Willi region of our DNA, the protein seems to act alone, they said.

So Langouet and Lalande took stem cells donated by Prader-Willi patients and carefully deleted ZNF274. They then encouraged the stem cells to grow into neurons, a type of brain cell. And the cells seemed normal. They grew and developed, as expected.

Critically, the new cells also expressed the maternal copy of the Prader-Willi region.

“We still need to figure out if knocking out ZNF274 is doing anything else” that might be undesirable, says Langouet.

And many other questions still need to be answered: Does this work directly in human brain cells? Will it only work in embryos, or can it help the brain develop normally even after birth?

Currently, there is no cure for Prader-Willi syndrome, and most research has been targeted towards treating specific symptoms. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as the insatiable appetite and obesity, would represent a significant improvement in quality of life and the ability to live independently.

But in the future, this new line of research may offer a therapeutic approach for kids with Prader-Willi, Langouet says.

The research was funded by the Foundation for Prader-Willi Research, the Cascade Fellowship, and the CT Regenerative Medicine Fund.

Early Dependency Leads to Lower Achievement

A new study has found that young adults who are dependent on marijuana and alcohol are less likely to achieve adult life goals. UConn Health scientists from the psychiatry department analyzed data from the National Institute of Alcohol Abuse and Alcoholism’s Collaborative Study on the Genetics of Alcoholism (COGA) and found that these substance-dependent young adults go on to have lower levels of education, decreased rates of full-time employment, less marriage potential, and less social economic potential. The study, presented at the American Public Health Association 2017 Annual Meeting & Expo, also found that marijuana and alcohol dependency may have a more severe effect on young men, affecting them in all areas of measure versus women, who were less likely to obtain a college degree and had lower economic potential, but were equally likely to get married or obtain full-time employment.

Biodegradable Sensor Monitors Pressure, Disappears

A patent is pending for a biodegradable pressure sensor developed by UConn engineers that could help doctors monitor chronic lung disease, swelling of the brain, and other medical conditions, before dissolving harmlessly in a patient’s body. The small, flexible sensor is made of medically safe materials already approved by the U.S. Food and Drug Administration for use in surgical sutures, bone grafts, and medical implants. It is designed to replace existing implantable pressure sensors that have potentially toxic components and require an additional invasive procedure to remove, extending patients’ recovery time and increasing the risk of infection. The research was funded by a National Institutes of Health grant and funds from UConn’s Academic Plan and is featured online in the Proceedings of the National Academy of Sciences.

DNA Becomes Harder to Access as We Age

A comparison between the immune cells of seniors ages 65 and over and those of adults between the ages of 22 and 40 has revealed that DNA changes with age, impacting how the immune system renews itself. In the sample from the aging population, chromosomes appeared more tightly coiled, making it difficult for cells to access the DNA that might be critical in defending our bodies against diseases, including flu and some cancers. In contrast, the regions of chromosome coding for genes associated with cell death and inflammation appeared to be more open in the elderly than in the young. The study, conducted by a team from UConn Health and the Jackson Laboratory for Genomic Medicine, appeared in the Journal of Experimental Medicine.

Portable Microscope a Game Changer in the Field

UConn optical engineers have developed a portable holographic microscope that enables medical professionals to identify diseased cells and other biological specimens in the field in just minutes. The detailed holograms generated by the microscope can be used by medical workers attempting to identify malaria patients in remote areas of Africa and Asia, where the disease is endemic. It also can be used in hospitals and other clinical settings for rapid analysis of cell morphology and cell physiology associated with cancer, hepatitis, HIV, sickle cell disease, heart disease, and other illnesses. The device was recently featured in a paper published by Applied Optics.

An earlier study by Dr. Andrew Arnold (center) provided the basis for the new research on parathyroid carcinoma genes.

An international team of scientists led by the UConn School of Medicine and Icahn School of Medicine at Mount Sinai sequenced a genome for an extremely rare form of cancer, demonstrating the utility of this approach in opening the door for therapy options for rare diseases that are neglected due to scarcity of patients or lack of resources.

The team’s findings were published by JCI Insight, a journal of the American Society for Clinical Investigation.

Leading genomic scientists from UConn, Mount Sinai, and other collaborating institutions performed exome sequencing on tumors and matched normal samples from 17 patients with parathyroid carcinoma, an ultra-rare form of cancer for which there is no effective treatment.

Researchers found several mutations in known cancer-related genes and pathways. This in-depth characterization provides a clear view of genetic mechanisms involved in parathyroid carcinoma and could lead to the first therapy options for patients.

The genetic variants identified in this study have been detected in other cancers and are the subject of ongoing “basket” trials, or clinical trials focused on specific mutations rather than the tissue where the cancer formed.

“This is the largest genomic sequencing study to date for this rare and deadly cancer, and we believe it serves as important validation for using this approach to uncover clinically relevant information in any number of neglected diseases,” said Rong Chen, senior author of the paper and assistant professor in the Department of Genetics and Genomic Sciences at Mount Sinai. “Genomic analysis is opening the doors to diseases that could never have been understood through traditional biomedical research because there simply aren’t enough patients to observe.”

Mount Sinai’s work built upon research by Dr. Andrew Arnold of UConn, published in the New England Journal of Medicine in 2003. In the earlier study, Arnold reported on the first gene discovered in non-familial parathyroid cancer.

“Some of the tumor-specific genomic vulnerabilities we found turn out to be shared with much more common cancers, so drugs already being developed for other cancers may prove valuable in parathyroid cancer,” said Arnold, the study’s co-leader, who serves as the Murray-Heilig Chair in Molecular Medicine, director of the Center for Molecular Medicine, and chief of endocrinology at UConn School of Medicine. “This offers new hope for our patients and serves as a model for approaching other rare and neglected diseases.”

The study was funded by the Icahn Institute of Genomics and Multiscale Biology at Mount Sinai and the Murray-Heilig Fund in Molecular Medicine at UConn School of Medicine through the UConn Foundation.

UConn Health research image of a parathyroid gland (darker) located on the thyroid gland (pink background) during a research experiment where scientists genetically engineered mouse models, knocking out the CDC73 gene to test if cancer would then develop.

UConn has awarded $300,174 to seed a new Professional Science Master’s (PSM) Program in Genetics, Genomics, and Counseling. Graduates of the program will work with doctors and patients to interpret the results of genetic testing, a rapidly growing area in health care that needs more trained personnel. Once accredited, the program will be the first in Connecticut and the only one in New England at a public institution.

“Our students are anxious. They want to do this,” says Judy Brown, director of the diagnostic genetic sciences program in UConn’s College of Agriculture, Health, and Natural Resources’ allied health sciences department. Brown is spearheading the push for the program along with Institute for Systems Genomics director Marc Lalande and UConn Health genetics counselor Ginger Nichols.

Once accredited, the program will be the first in Connecticut and the only one in New England at a public institution.

New genetics research and techniques have made it easy for the average person to get a read on their genome, or whole genetic code. Celebrities, including Angelina Jolie, who have openly discussed their genetic risk factors for cancer, and companies, such as 23andMe, that will provide a basic genetic report for a fee, have increased demand enormously. But there’s a lack of trained people who can accurately interpret and explain the results of genetic tests, limiting the potential benefits.

Ideally, a doctor who identifies “red flags” within a patient’s family history that indicate increased genetic risk for disease will call in a genetic counselor. The counselor can take a detailed family history, determine the appropriateness of genetic testing, discuss benefits and limitations of testing to help the patient make an informed decision, and advise the patient on who else in their family might be at risk. If testing occurs and results indicate high genetic risk, counselors can help discuss the options to mitigate that risk.

As a result, genetic counseling is the fourth-fastest-growing occupation in Connecticut. Many UConn allied health sciences majors would like to enter the profession, Brown says, but there are only 34 training programs in the U.S., and the acceptance rate is below 8 percent.

Institutions including Connecticut Children’s Medical Center and The Jackson Laboratory (JAX) have expressed support for the program. Kate Reed, director of the Clinical and Continuing Education Program at JAX, says JAX would combine its experience translating genetic discoveries into clinical applications with UConn’s experience in this area to give the PSM graduates a solid understanding of the research behind clinical treatments.

The exact roles of JAX, Connecticut Children’s, and the other institutions who support the new PSM have not yet been defined. The program’s curriculum first needs to be approved and accredited. The first students are expected to start the program in fall 2018.

Cancer Cells Unreceptive to Vitamin D

Many human colon cancers may not express receptors for vitamin D, limiting vitamin D’s protective role against colon cancer to the early stages of the disease, report Charles Giardina and colleagues at UConn’s Department of Molecular and Cell Biology and Center for Molecular Medicine in the April 14 issue of Cancer Prevention Research. The researchers observed that adenomas in the colons of mice tended to repress vitamin D receptors, while having elevated Class I histone deacetylases (HDAC). However, HDAC inhibitors may reactivate the vitamin D receptors. They propose that vitamin D could still be protective against colon cancer, but how its receptors are expressed and inhibited in cancer cells needs more examination. Read the article at Cancer Prevention Research.

Rogue X Chromosomes Uncovered in Farmington

Humans only need the genes from one X chromosome to be healthy. The extra one gets trussed up and shut down in the earliest stages of development. But female human embryonic stem cells growing in the lab sometimes reactivate their second X. They express extra genes, fouling up experiments and scuttling potential therapies. Now, researchers including UConn’s Marc Lalande and a team from Paris Diderot University have found a marker, and potentially a mechanism, for how the extra X reactivates – and they have an idea on how to prevent it. They describe their findings in the May 7 issue of Cell Stem Cell.

Friends are Unreliable Sources for Drinking Studies

In recent years, researchers have turned to friends of people in alcohol studies to verify what the subjects report about their drinking habits. People in the same social situations are sought out, in part, because of the inherent impairment caused by alcohol. But according to a UConn study published in Addictive Behaviors, friends don’t seem to provide any new information. In fact, they typically underreport what their acquaintances consume. The finding supports the so-called “protective effect” of friends described in other research. A growing availability of other evidence – hair and fingernail samples, for example – may provide better strategy for corroborating the amount of alcohol study subjects consume, says author Michael Fendrich, associate dean of the School of Social Work.

She Smells Him, She Smells Him Not

Mice rely on their noses to help them navigate the world. But high levels of progesterone “blind” receptors in the noses of female mice to male pheromones, UConn Health’s John Peluso and other colleagues, led by Dr. Lisa Stowers of The Scripps Research Institute, report in the June 4 issue of Cell. Female mice have high levels of progesterone during the infertile phase of their reproductive cycles, and tend to be indifferent or even aggressive toward males. But during the fertile phase, progesterone levels drop and estrogen rises, and their nasal receptors again respond to male pheromones, the researchers found. Female mice in their fertile phase are friendly and sexually receptive towards males – perhaps because they can smell them.